The present invention relates, in general, to compositions and methods aimed at effectively treating anaerobic tumor cells with inhibitors of glycolysis. It also extends to novel and useful methods and compositions for treating aerobic tumor cells with inhibitors of oxidative phosphorylation in combination with glycolytic inhibitors. Inhibiting oxidative phosphorylation to convert aerobic tumor cells to anaerobic cells, hypersensitizes them to glycolytic inhibitors.
U.S. patents that are relevant to the compositions and methods of the present invention are: U.S. Pat. Nos. 4,840,939 and 4,684,627, both for a treatment of cancer with phlorizin and its derivatives; U.S. Pat. No. 4,683,222 for N-glycosylated carboxamide derivatives and their use for influencing the body's inherent defenses; and U.S. Pat. No. 4,420,489 for sugars with sulfur replacing the ring oxygen atom as antiradiation agents. U.S. Pat. No. 4,840,939 is also relevant for its discussion of the work of Warburg in 1931, concerning the way cancer cells metabolize glucose.
Cancer cells at the inner core of a tumor are poorly oxygenated and consequently rely on anaerobic metabolism for survival. In this condition tumor cells divide more slowly than outer growing aerobic cells and consequently are more resistant to standard chemotherapeutic agents which target rapidly dividing cells. Thus, cells growing anaerobically in these instances exhibit a form of multidrug resistance (MDR) which contributes to chemotherapy failures in the treatment of solid tumors. Anaerobiosis, however, also provides a natural window of selectivity for agents that interfere with glycolysis.
This realization forms the basis for the present invention. According to the present invention, new opportunities are provided for increasing the efficacy of chemotherapeutic protocols. With data and knowledge accumulated by us in our previous work on mitochondrial agents, and with additional work performed by us now, various hypotheses have been formulated and verified to prove the efficacy of the present invention with regard to its compositions and its methods.
See, for example, a series of papers coauthored by one of the present inventors: Lampidis, T J, Bernal, S D, Summerhayes, I C, and Chen, L B. “Rhodamine 123 is selectively toxic and preferentially retained in carcinoma cells in vitro.” NY Acad. Sci. 397: 299–302, 1982; Summerhayes, I C, Lampidis, T J, Bernal, S D, Shepherd, E L, and Chen, L B. “Unusual retention of Rhodamine 123 by mitochondria in muscle and carcinoma cells.” Proc. Natl. Acad. Sci. USA 79: 5292–5296, 1982; Bernal, S B, Lampidis, T J, Summerhayes, I C, and Chen, L B. “Rhodamine 123 selectively reduces clonogenic ability of carcinoma cells in vitro.” Science. 218:1117–1119, 1982; Lampidis, T J, Bernal, S D, Summerhayes, I C, and Chen, L B. “Selective toxicity of Rhodamine 123 in carcinoma cells in vitro.” Cancer Res. 43:716–720, 1983; and Bernal, S B, Lampidis, T J, Mclsaac, B, and Chen, L B. “Anticarcinoma activity in vivo of Rhodamine 123, a mitochondrial-specific dye.” Science. 222: 169–172, 1983; which showed that Rhodamine 123 (Rho 123) which localizes in mitochondria of living cells, and uncouples ATP synthesis from electron transport, preferentially accumulates in, and kills, a variety of tumor cells as compared to a number of normal cells. We reasoned for the present invention that tumor cells treated with this drug would have to rely solely on glycolysis for ATP production and thus become hypersensitized to inhibitors of glycolysis, like 2-dg (2-dg). In contrast, mitochondrial function in normal cells remained unaffected when treated with Rho 123 and therefore these cells were not hypersensitive to 2-dg. In fact, we found that co-treating human breast carcinoma cells, MCF-7, with Rho 123 and 2-dg, at a dose of Rho 123 that alone inhibited 50% of colony forming units, and at a dose of 2-dg which produced no toxicity, 100% of the colony forming units was inhibited.
This concept was carried over to in vivo studies in which it was found that animals with implanted tumors that were treated in combination with 2-dg and Rho 123 were cured whereas when treated with either drug alone, only partial or no responses were obtained. This latter result provides evidence that manipulation of Oxphos and glycolysis simultaneously can cure tumors in animals. Furthermore, this in vivo data also demonstrates that 2-deoxyglocose can be administered safely to animals, at doses which are effective for anti-tumor activity in combination with an Oxphos inhibitor. In this regard, several reports have shown that low levels of 2-dg can be safely administered to animals for various reasons including hypersensitization of tumors to irradiation.